tTF-NGR Randomized Study - STS

Summary

In this phase III open label, controlled clinical trial patients with unresectable or metastatic soft-tissue sarcoma after failure of anthracycline-containing first line therapy or with contraindications to these drugs and CD13 positivity in central histology (grade \>/= 1+) are treated to evaluate whether tTF-NGR in combination with standard trabectedin chemotherapy prolongs progression-free survival (according to iRECIST), as compared with trabectedin alone. Further objectives are to evaluate the efficacy of tTF-NGR in combination with standard trabectedin chemotherapy with respect to the response rate and overall survival as well as to assess the safety profile of tTF-NGR combined with trabectedin. Before the randomized phase III part of the study, there was a safety run-in part. The final dose of tTF-NGR established as safe in this safety run-in part is 0.5 mg/m2 per day for 2 consecutive days following each trabectedin infusion and is used for the randomized (parallel 1:1; Arm 1: standard trabectedin, Arm 2: standard trabectedin plus tTF-NGR) phase III part of this trail. . Further dose modification for tTF-NGR is possible.

Eligibility

Inclusion Criteria:

1. Patients of all genders (female, male, diverse), with no restriction regarding ethnic or religious background age 18 - 75 years.
2. Patients with advanced or metastatic soft-tissue sarcoma after failure of anthracycline-containing first line therapy (or anthracycline-containing adjuvant therapy within 12 months before entry on study) or with contraindications to these drugs
3. Patients must have histological evidence of high-grade advanced unresectable or metastatic soft tissue sarcoma (grade 2 - 3) according to the FNCLCC grading system. The following tumor types are included:

   * Dedifferentiated liposarcoma
   * Myxoid liposarcoma (high grade)
   * Pleomorphic liposarcoma
   * Adult fibrosarcoma
   * Myxofibrosarcoma (high-grade)
   * Leiomyosarcoma
   * Rhabdomyosarcoma (alveolar, pleomorphic)
   * Angiosarcoma
   * Synovial sarcoma
   * Undifferentiated sarcoma

   Tumor types not listed above may be included upon communication with Coordinating Investigator.

   The following tumor types will not be included:
   * Gastrointestinal stromal tumors (GIST)
   * Epitheloid sarcoma
   * Alveolar soft part sarcoma
   * Desmoplastic small round cell tumor
   * Chondrosarcoma
   * Osteosarcoma
   * Ewing sarcoma (including CIC-rearranged sarcoma and Sarcoma with BCOR alterations)
4. CD13 positivity with a score of ≥ 1 (20) by central pathology (GDI Münster)
5. Patients must have at least one unidimensionally measurable lesion by computed tomography as defined by RECIST criteria 1.1. Other adequate imaging procedures such as MRI are allowed. This lesion should not have been irradiated during previous treatments
6. Life expectancy of at least 3 months
7. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
8. No contraindications for trabectedin (see attachment)
9. Negative serum pregnancy test for females of childbearing potential\* within 14 days of starting treatment
10. Informed consent signed and dated to participate in the study
11. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures

    * Women of childbearing potential (WOCBP) must be using, from the screening to 3 months following the last trabectedin (Arm 1) or the last last study drug (Arm 2) administration, highly effective contraception methods, as defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group (www.hma.eu/ctfg.html) and which include, for instance, progesteron-only or combined (estrogen- and progesteron-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence. Pregnancy test will be repeated monthly. For men contraception methods should be performed for 5 months after the last application of trabectedin (Arm1) or study drug (Arm 2).Women of childbearing potential are defined as females who have experienced menarche, are not postmenopausal (12 months with no menses without an alternative medical cause) and are not permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy)

Exclusion Criteria:

1. curative therapy available
2. clinically significant unrelated illness, which in the judgement of the investigators could compromise the patient's ability to tolerate the IMP or be likely to interfere with the study procedures or results
3. immobilized tumor patients (wheel chair etc.) with increased risk for DVT
4. known hypersensitivity reactions to prior application of E. coli-derived material
5. history of coronary heart disease, stroke, transitent ischemic attacks, pulmonary embolism, or deep vein thrombosis. For reason of mechanism of action of tTF-NGR, exclusion of patients with a history of any of the vascular conditions mentioned is important. Clinical suspicion of coronary heart disease must be further checked e.g. by cardiac MRI or myocardial scintigraphy to exclude coronary heart disease.
6. known hereditary syndromes with elevated thromboembolic risk (FV Leiden and prothrombin mutations (G20210A), hereditary antithrombin, protein C and S deficiency, and antiphospholipid syndrome) after one or more clinical thromboembolic events
7. patients with hereditary vascular disorders (such as Klippel-Trenauny-Weber syndrome) with increased thromboembolic risk.
8. patients with a Khorana score of (Khorana AA, et al. J.Clin. Oncol. 2009, 27, 4839-4847, attached to this protocol) of \> 3
9. elevated Troponin T hs (\> 50 ng/L) or elevated Troponin I hs before entry on study
10. presence of active central nervous system (CNS) disease and/or CNS vascular abnormalities detected by MRI or CT
11. no adequate bone marrow function, absolute neutrophil count (ANC) \< 1.0 x 109/L, platelets \< 50 x 109/L (for trabectedin actually \< 100 x 109/L - to be decided by the investigator on an individual patient basis) and haemoglobin (Hb) \< 8.0 g/dl.
12. chronically impaired renal function or creatinine ≥ 2.0 x upper limit of normal (ULN).
13. inadequate liver function (alanine aminotranserase (ALT), aspartate aminotranserase (AST), alkaline phosphatase (ALP) or total bilirubin ≥ 2.5 x ULN) unless due to liver metastasis (decision by the investigator)
14. fibrinogen \< 150 mg/dL, and/or International Normalized Ratio (INR) \> 1,5 (global coagulation parameters can be discussed with the Coordinating Investigator prior to entry on study)
15. female patients with child-bearing who do not agree to exclusion of potential pregnancy by adequate testing within 48 hours prior to entry on study
16. females of childbearing potential as well as fertile males who do not agree to use a highly effective form of contraception (Pearl Index \< 1) during the study and for 3 months (females) following the last trabectedin (Arm 1) or last study drug (Arm 2) administration and 5 months (males) following the last dose of trabectedin (Arm 1) or study drug (Arm 2)
17. women with breast-feeding activity
18. concomitant use of any other investigational agent (agent for which there is currently no approved indication from regulatory authorities) or any other anti-cancer drug
19. concomitant enrolment in another clinical trial interfering with the endpoints of this study.
20. any medical condition which could compromise participation in the study according to the investigator's assessment.
21. prophylactic or therapeutic anticoagulation within the last 3 days
22. presence of active and uncontrolled infections or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study
23. concurrent malignancies other than STS, unless the patient has been disease-free for at least 2 years
24. serious, non-healing wound, ulcer or bone fracture; not completed wound healing from previous wounds and/or surgery
25. no central venous port system in place (the option of other central venous access than a port should be discussed with the Coordinating Investigator).

NOTE: Outliers of laboratory values can be disregarded and set aside as exclusion criteria by a Coordinating Investigator´s decision. The conditions for the use of trabectedin as specified in the Summary of Product Characteristics are to be followed according to institutional guidelines for standard of care.

Conditions2

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